Oxygenator of a hollow fiber membrane type using porous membrane has been widely used in general as an extracorporeal circulation device and an artificial cardiopulmonary device for auxiliary circulation in an open heart surgery for cardiac diseases. In an oxygenator of a membrane type, hollow fiber membrane is mostly used and gas exchange of the blood is conducted via the hollow fiber membrane. As a method for perfusion of the blood to an oxygenator, there are an internal perfusion method where the blood is flown to the inner side of the hollow fiber membrane while gas is flown to the outer side of the hollow fiber membrane and an external perfusion method in a reversed manner where the blood is flown to the outer side of the hollow fiber membrane while gas is flown to the inner side of the hollow fiber membrane.
In the oxygenator of an external perfusion type, the gas exchanging ability per membrane surface is higher and the loss in pressure is less than the oxygenator of an internal perfusion type whereby it has becoming the main stream. However, it has been difficult to suppress the activation of a complement system (the blood protein of immune system) caused by the result of recognition of foreign body by contacting the blood to hollow fiber membrane.
For example, an oxygenator coated with a composite of benzylalkylammonium with heparin has been disclosed (Patent Document 1). However, there is a disadvantage that the coating agent is detached into the blood during the use.
It has been also tried to cover with a hydrophilic polymer but, when porous membrane is used as a gas exchange membrane, there is a case where plasma components are permeated into the pore to cause the leakage of plasma whereupon gas exchanging ability lowers.
An oxygenator where a surface treatment with alkoxyalkyl (meth)acrylate has been disclosed as well (Patent Document 2). In preparing a coating solution of said alkoxyalkyl (meth)acrylate, the use of methanol which is a toxic substance is essential and there is a problem of elution of methanol remaining in the oxygenator into the blood and there is also a problem that long time and high cost are needed for a complete removal of methanol from the oxygenator.
Further, a water-soluble copolymer of polyethylene glycol(meth)acrylate and alkyl(meth)acrylate has been known (Patent Document 3). With this technique, protection of a surface of a solid phase can be performed in immunoassay. However, since this copolymer is water-soluble, long-term maintenance of biocompatibility was difficult.
In the synthesis of polymers, re-precipitation has been most easily and conveniently used as a method for the separation of low-molecular substances (such as monomer and oligomer) from copolymer, polymer, etc. However, no method for purification of (co)polymer by means of re-precipitation from a mixture of hydrophilic monomer, hydrophobic monomer and water-insoluble (co)polymer has been known yet.
As to a method of applying a (co)polymer to medical devices, a method where the (co)polymer is dissolved in an organic solvent such as ethanol, tetrahydrofuran or acetone and the resulting solution is applied to the medical device following by drying has been generally known. However, a medical tube made of, for example, plasticized polyvinyl chloride contains a phthalate as a plasticizer and, when an organic solvent solution is contacted, the plasticizer is easily dissolved out and the tube hardens or the tube itself is swollen whereupon deformation or crack is resulted. Thus, that has a problem in terms of quality of the product.
As to a water-insoluble polymer which is compatible with the blood, a copolymer of alkoxyalkyl acrylate with alkyl (meth)acrylate has been known but, in that case, a specific copolymer is used (Patent Documents 4 and 5).
It has been also known that a copolymer containing a vinyl monomer having ethylene glycol chain in a molecule is used for a specific use which is a dispersing agent for a suspension polymerization (Patent Document 4) and, further, a copolymer containing a unsaturated polymerizing monomer of ethylene type having an acrylic alkylene glycol residue and the use of a biochip material using said copolymer (i.e. a polymer compound which fixes a physiologically active substance) have been known as well (Patent Document 6).
A biocompatible composition comprising a nonionic polymer having a glass transition point of not higher than 300K and an organism-derived material having an anticoagulant activity has been known (Patent Document 7). However, since an organism-derived material is an essential ingredient in this composition, no consideration is done for the problems of infection and safety.
There has been known a product where alkoxyalkyl (meth)acrylate is subjected to a surface treatment to a part where an oxygenator of a hollow fiber membrane external perfusion type contacts with the blood (Patent Document 2). However, since this (meth)acrylate has a more hydrophilicity, there is a risk that it is easily eluted into the blood.
There has been known an art where adsorption of protein is suppressed by a copolymer of methoxy polyethylene oxide methacrylate with alkyl methacrylate (Nonpatent Document 1). However, since this copolymer has a more hydrophilicity, there is a problem that it is dissolved in the blood.
As a coating material for suppressing the adsorbed amount of protein, a copolymer of methyl methacrylate with methoxy polyethylene oxide methacrylate has been known (Nonpatent Document 2). However, since hydrophobicity is resulted using methyl methacrylate where carbon number of the alkyl group is 1, polyethylene glycol chain is unable to be sufficiently introduced whereby there is a problem that no sufficient compatibility with blood is able to be achieved.
A surface treating agent for medical devices comprising a hydrophilic-hydrophobic block copolymer has been known (Nonpatent Document 3). However, since this copolymer has a more hydrophilicity and is easily eluted into the blood, there is a problem that the effect does not continue for a long period of time.
A block copolymer of oligoethylene glycol methacrylate with octadecyl acrylate has been known (Nonpatent Document 4). However, since the copolymer is solid at room temperature, there is a problem that, after the coating is done, it is physically detached from the medical device.
There has been known a filter agent by which leucocytes are selectively removed where the agent comprises a copolymer of methoxy polyethylene glycol methacrylate with methyl methacrylate (Patent Document 8). However, since this copolymer has a more hydrophilicity and is easily eluted into the blood, there is a problem that the effect does not continue for a long period of time.
There has been known a biocompatible lubricant hydrophilic material comprising a copolymer of methoxy polyethylene glycol methacrylate with alkyl methacrylate (Patent Document 9). However, since this copolymer has a more hydrophilicity and is easily eluted into the blood, there is a problem that the effect does not continue for a long period of time.
There has been known a copolymer comprising methoxy polyethylene glycol (meth)acrylate with alkyl (meth)acrylate (Patent Document 10). However, since the copolymer is solid at room temperature, there is a problem that, after the coating is done, it is physically detached from the medical device.
There has been known an antithrombotic surface treating agent comprising alkoxyalkyl (meth)acrylate (Patent Documents 5 and 11). However, since this copolymer has a more hydrophilicity and is easily eluted into the blood, there is a problem that the effect does not continue for a long period of time.